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Potential impact of tuberculosis vaccines in China, South Africa, and India

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (564)

More effective tuberculosis vaccines are needed to help reach World Health Organization tuberculosis elimination goals. Insufficient evidence exists on the potential impact of future tuberculosis vaccines with varying characteristics and in different epidemiological settings. To inform vaccine development decision making, we modeled the impact of hypothetical tuberculosis vaccines in three high-burden countries. We calibrated Mycobacterium tuberculosis (M.tb) transmission models to age-stratified demographic and epidemiological data from China, South Africa, and India. We varied vaccine efficacy to prevent infection or disease, effective in persons M.tb uninfected or infected, and duration of protection. We modeled routine early-adolescent vaccination and 10-yearly mass campaigns from 2025. We estimated median percentage population-level tuberculosis incidence rate reduction (IRR) in 2050 compared to a no new vaccine scenario. In all settings, results suggested vaccines preventing disease in M.tb-infected populations would have greatest impact by 2050 (10-year, 70% efficacy against disease, IRR 51%, 52%, and 54% in China, South Africa, and India, respectively). Vaccines preventing reinfection delivered lower potential impact (IRR 1, 12, and 17%). Intermediate impact was predicted for vaccines effective only in uninfected populations, if preventing infection (IRR 21, 37, and 50%) or disease (IRR 19, 36, and 51%), with greater impact in higher-transmission settings. Tuberculosis vaccines have the potential to deliver substantial population-level impact. For prioritizing impact by 2050, vaccine development should focus on preventing disease in M.tb-infected populations. Preventing infection or disease in uninfected populations may be useful in higher transmission settings. As vaccine impact depended on epidemiology, different development strategies may be required.

Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (524)

Circulating tumor DNA (ctDNA) has emerged as a useful diagnostic and prognostic biomarker in many cancers. Here, we conducted a study to investigate the potential use of ctDNA methylation markers for the diagnosis and prognostication of colorectal cancer (CRC) and used a prospective cohort to validate their effectiveness in screening patients at high risk of CRC. We first identified CRC-specific methylation signatures by comparing CRC tissues to normal blood leukocytes. Then, we applied a machine learning algorithm to develop a predictive diagnostic and a prognostic model using cell-free DNA (cfDNA) samples from a cohort of 801 patients with CRC and 1021 normal controls. The obtained diagnostic prediction model discriminated patients with CRC from normal controls with high accuracy (area under curve = 0.96). The prognostic prediction model also effectively predicted the prognosis and survival of patients with CRC (P < 0.001). In addition, we generated a ctDNA-based molecular classification of CRC using an unsupervised clustering method and obtained two subgroups of patients with CRC with significantly different overall survival (P = 0.011 in validation cohort). Last, we found that a single ctDNA methylation marker, cg10673833, could yield high sensitivity (89.7%) and specificity (86.8%) for detection of CRC and precancerous lesions in a high-risk population of 1493 participants in a prospective cohort study. Together, our findings showed the value of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of CRC.

Pancreatitis is an FGF21-deficient state that is corrected by replacement therapy

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (525)

The exocrine pancreas expresses the highest concentrations of fibroblast growth factor 21 (FGF21) in the body, where it maintains acinar cell proteostasis. Here, we showed in both mice and humans that acute and chronic pancreatitis is associated with a loss of FGF21 expression due to activation of the integrated stress response (ISR) pathway. Mechanistically, we found that activation of the ISR in cultured acinar cells and mouse pancreata induced the expression of ATF3, a transcriptional repressor that directly bound to specific sites on the Fgf21 promoter and resulted in loss of FGF21 expression. These ATF3 binding sites are conserved in the human FGF21 promoter. Consistent with the mouse studies, we also observed the reciprocal expression of ATF3 and FGF21 in the pancreata of human patients with pancreatitis. Using three different mouse models of pancreatitis, we showed that pharmacologic replacement of FGF21 mitigated the ISR and resolved pancreatitis. Likewise, inhibition of the ISR with an inhibitor of the PKR-like endoplasmic reticulum kinase (PERK) also restored FGF21 expression and alleviated pancreatitis. These findings highlight the importance of FGF21 in preserving exocrine pancreas function and suggest its therapeutic use for prevention and treatment of pancreatitis.

Plasma exosomal miR-375-3p regulates mitochondriadependent keratinocyte apoptosis by targeting XIAP in severe drug-induced skin reactions

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (574)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug-induced cutaneous reactions characterized by keratinocyte apoptosis. Exosomes are nanometer-sized membranous vesicles in body fluids. They contain functional proteins, mRNAs, and miRNAs, which induce immune dysfunction and influence disease progression. However, their roles and mechanisms in SJS/TEN remain unknown. Our results demonstrate that exosomes isolated from the plasma of patients with SJS/TEN were 30 to 200 nm in diameter and expressed CD9, CD63, CD81, and TSG101 exosome marker proteins. miR-375-3p was markedly up-regulated in 35 patients with SJS/ TEN and correlated with clinical severity. Plasma exosomes were internalized by human primary keratinocytes and promoted keratinocyte apoptosis in vitro. Furthermore, miR-375-3p overexpression promoted intrinsic (mitochondria-dependent) apoptosis of human primary keratinocytes via down-regulation of the X-linked inhibitor of apoptosis protein (XIAP), a key apoptosis regulator in primary human keratinocytes. In sum, our study indicates that the circulating exosomal miR-375-3p enters keratinocytes, down-regulates XIAP, and induces keratinocyte apoptosis in patients with SJS/TEN.

Wireless sensors for continuous, multimodal measurements at the skin interface with lower limb prostheses

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (574)

Precise form-fitting of prosthetic sockets is important for the comfort and well-being of persons with limb amputations. Capabilities for continuous monitoring of pressure and temperature at the skin-prosthesis interface can be valuable in the fitting process and in monitoring for the development of dangerous regions of increased pressure and temperature as limb volume changes during daily activities. Conventional pressure transducers and temperature sensors cannot provide comfortable, irritation-free measurements because of their relatively rigid construction and requirements for wired interfaces to external data acquisition hardware. Here, we introduce a millimeter-scale pressure sensor that adopts a soft, three-dimensional design that integrates into a thin, flexible battery-free, wireless platform with a built-in temperature sensor to allow operation in a noninvasive, imperceptible fashion directly at the skin-prosthesis interface. The sensor system mounts on the surface of the skin of the residual limb, in single or multiple locations of interest. A wireless reader module attached to the outside of the prosthetic socket wirelessly provides power to the sensor and wirelessly receives data from it, for continuous long-range transmission to a standard consumer electronic device such as a smartphone or tablet computer. Characterization of both the sensor and the system, together with theoretical analysis of the key responses, illustrates linear, accurate responses and the ability to address the entire range of relevant pressures and to capture skin temperature accurately, both in a continuous mode. Clinical application in two prosthesis users demonstrates the functionality and feasibility of this soft, wireless system.

Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (574)

Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance is a prognostic indicator for cancer severity, therapy resistance, and shortened patient survival. The HSF1 gene was amplified, and nuclear HSF1 abundance was markedly increased in prostate cancers and particularly in neuroendocrine prostate cancer (NEPC), for which there are no available treatment options. Despite genetic validation of HSF1 as a therapeutic target in a range of cancers, a direct and selective small-molecule HSF1 inhibitor has not been validated or developed for use in the clinic. We described the identification of a direct HSF1 inhibitor, Direct Targeted HSF1 InhiBitor (DTHIB), which physically engages HSF1 and selectively stimulates degradation of nuclear HSF1. DTHIB robustly inhibited the HSF1 cancer gene signature and prostate cancer cell proliferation. In addition, it potently attenuated tumor progression in four therapy-resistant prostate cancer animal models, including an NEPC model, where it caused profound tumor regression. This study reports the identification and validation of a direct HSF1 inhibitor and provides a path for the development of a small-molecule HSF1-targeted therapy for prostate cancers and other therapy-resistant cancers.

Multimodal imaging of bacterial-host interface in mice and piglets with Staphylococcus aureus endocarditis

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (568)

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus that colonizes the heart's valves. S. aureus relies on virulence factors to evade therapeutics and the host's immune response, usurping the host's clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor-binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor-binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (568)

Autoimmune diseases such as multiple sclerosis (MS) develop because of failed peripheral immune tolerance for a specific self-antigen (Ag). Numerous approaches for Ag-specific suppression of autoimmune neuroinflammation have been proven effective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. One such approach is intravenous tolerance induction by injecting a myelin Ag used for triggering EAE. However, the translation of this and similar experimental strategies into therapy for MS has been hampered by uncertainty regarding relevant myelin Ags in MS patients. To address this issue, we developed a therapeutic strategy that relies on oligodendrocyte (Ol)-derived extracellular vesicles (Ol-EVs), which naturally contain multiple myelin Ags. Intravenous Ol-EV injection reduced disease pathophysiology in a myelin Ag-dependent manner, both prophylactically and therapeutically, in several EAE models. The treatment was safe and restored immune tolerance by inducing immunosuppressive monocytes and apoptosis of autoreactive CD4(+) T cells. Furthermore, we showed that human Ols also released EVs containing most relevant myelin Ags, providing a basis for their use in MS therapy. These findings introduce an approach for suppressing central nervous system (CNS) autoimmunity in a myelin Ag-specific manner, without the need to identify the target Ag.

Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (529)

Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K-null mice, as well as cathepsin K-mutant humans, continue to remodel bone and degrade collagen by as-yet-undefined effectors. Here, we identify a cathepsin K-independent collagenolytic system in osteoclasts that is composed of a functionally redundant network of the secreted matrix metalloproteinase MMP9 and the membrane-anchored matrix metalloproteinase MMP14. Unexpectedly, whereas deleting either of the proteinases individually leaves bone resorption intact, dual targeting of Mmp9 and Mmp14 inhibited the resorptive activity of mouse osteoclasts in vitro and in vivo and human osteoclasts in vitro. In vivo, Mmp9/Mmp14 conditional double-knockout mice exhibited marked increases in bone density and displayed a highly protected status against either parathyroid hormone- or ovariectomy-induced pathologic bone loss. Together, these studies characterize a collagenolytic system operative in mouse and human osteoclasts and identify the MMP9/MMP14 axis as a potential target for therapeutic interventions for bone-wasting disease states.

Elevated plasma beta-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (530)

Sudden death could be the first symptom of patients with arrhythmogenic cardiomyopathy (AC), a disease for which clinical indicators predicting adverse progression remain lacking. Recent findings suggest that metabolic dysregulation is present in AC. We performed this study to identify metabolic indicators that predicted major adverse cardiac events (MACEs) in patients with AC and their relatives. Comparing explanted hearts from patients with AC and healthy donors, we identified deregulated metabolic pathways using quantitative proteomics. Right ventricles (RVs) from patients with AC displayed elevated ketone metabolic enzymes, OXCT1 and HMGCS2, suggesting higher ketone metabolism in AC RVs. Analysis of matched coronary artery and sinus plasma suggested potential ketone body synthesis at early-stage AC, which was validated using patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in vitro. Targeted metabolomics analysis in RVs from end-stage AC revealed a "burned-out" state, with predominant medium-chain fatty acid rather than ketone body utilization. In an independent validation cohort, 65 probands with mostly non-heart failure manifestations of AC had higher plasma beta-hydroxybutyrate (beta-OHB) than 62 healthy volunteers (P < 0.001). Probands with AC with MACE had higher beta-OHB than those without MACE (P < 0.001). Among 94 relatives of probands, higher plasma beta-OHB distinguished 25 relatives having suspected AC from nonaffected relatives. This study demonstrates that elevated plasma beta-OHB predicts MACE in probands and disease progression in patients with AC and their clinically asymptomatic relatives.

Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (530)

Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis increases the permeability of the blood-brain barrier to bilirubin and exacerbates its neurotoxicity. In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration. In mouse neonatal neurons, bilirubin exhibits limited toxicity but robustly potentiates the activity of acid-sensing ion channels (ASICs), resulting in increases in intracellular Ca2+ concentration, spike firings, and cell death. Furthermore, neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acidosis promoted long-term impairments in learning and memory and complex sensorimotor functions in vivo, which are largely attenuated in ASIC1a null mice. These findings suggest that targeting acidosis and ASICs may attenuate neonatal hyperbilirubinemia complications.

Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (531)

Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. In these patients, the presence of focal cortical malformations is associated with the occurrence of lifelong epilepsy, leading to severe neurological comorbidities. Here, we show that the expression of the actin cross-linking protein filamin A (FLNA) is increased in resected cortical tissue that is responsible for seizures in patients with FCDII and in mice modeling TSC and FCDII with mutations in phosphoinositide 3-kinase (PI3K)-ras homolog enriched in brain (Rheb) pathway genes. Normalizing FLNA expression in these mice through genetic knockdown limited cell misplacement and neuronal dysmorphogenesis, two hallmarks of focal cortical malformations. In addition, Flna knockdown reduced seizure frequency independently of mTOR signaling. Treating mice with a small molecule targeting FLNA, PTI-125, before the onset of seizures alleviated neuronal abnormalities and reduced seizure frequency compared to vehicle-treated mice. In addition, the treatment was also effective when injected after seizure onset in juvenile and adult mice. These data suggest that targeting FLNA with either short hairpin RNAs or the small molecule PTI-125 might be effective in reducing seizures in patients with TSC and FCDII bearing mutations in PI3K-Rheb pathway genes.

Long noncoding RNA SNHG12 integrates a DNA-PK-mediated DNA damage response and vascular senescence

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (531)

Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr(-/-) mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr(-/-) mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD(+), fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.

Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (531)

MYCN-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN-amplified NB.

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19

期刊: SCIENCE TRANSLATIONAL MEDICINE, 2020; 12 (570)

Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions. Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease. Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies). Case series have recently detected aPL antibodies in patients with COVID-19. Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti-beta(2) glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM. We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples. Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer's threshold and in 30% using a more stringent cutoff (>= 40 ELISA-specific units). Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate. Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals. Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models. These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.

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